Departments of Biochemistry and Molecular Medicine, Keck School of Medicine of University of Southern California, Los Angeles, CA, USA.
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Blood Rev. 2018 Jan;32(1):61-70. doi: 10.1016/j.blre.2017.08.008. Epub 2017 Aug 16.
Sickle cell anemia (SCA) is an autosomal recessive disorder caused by mutation in the β-globin gene. Pulmonary hypertension (PH), a complication of SCA, results in severe morbidity and mortality. PH is a multifactorial disease: systemic vasculopathy, pulmonary vasoconstriction, and endothelial dysfunction and remodeling. Placenta growth factor (PlGF), an angiogenic growth factor, elaborated from erythroid cells, has been shown to contribute to inflammation, pulmonary vasoconstriction and airway hyper-responsiveness (AH) in mouse models of sickle cell disease. In this review, we summarize the cell-signaling mechanism(s) by which PlGF regulates the expression of genes involved in inflammation, PH and AH in cell culture and corroborate these findings in mouse models of SCA and in individuals with SCA. The role of microRNAs (miRNAs) in the post-transcriptional regulation of these genes is presented and how these miRNAs located in their host genes are transcriptionally regulated. An understanding of the transcriptional regulation of these miRNAs provides a new therapeutic approach to ameliorate the clinical manifestations of SCA.
镰状细胞贫血症（SCA）是一种由β-球蛋白基因突变引起的常染色体隐性遗传病。肺高血压（PH）是 SCA 的一种并发症，可导致严重的发病率和死亡率。PH 是一种多因素疾病：全身血管病、肺血管收缩和内皮功能障碍及重塑。胎盘生长因子（PlGF）是一种血管生成生长因子，由红系细胞分泌，已被证明可导致镰状细胞病小鼠模型中的炎症、肺血管收缩和气道高反应性（AH）。在这篇综述中，我们总结了 PlGF 通过何种细胞信号机制调节细胞培养中参与炎症、PH 和 AH 的基因的表达，并在 SCA 小鼠模型和 SCA 个体中证实了这些发现。我们还介绍了 microRNAs（miRNAs）在这些基因的转录后调控中的作用，以及这些位于其宿主基因中的 miRNAs 如何被转录调控。了解这些 miRNAs 的转录调控为改善 SCA 的临床症状提供了一种新的治疗方法。
